Ординатура / Офтальмология / Английские материалы / Retinal Vascular Disease_Joussen, Gardner, Kirchhof_2007

References

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4.Central Retinal Vein Occlusion Study Group (1993) Baseline and early natural history report. The Central Retinal Vein Occlusion Study. Arch Ophthalmol 11:1087 – 95

5.Brown GC, Magargal LE, Schachat A, Shah H (1984) Neovascular glaucoma. Etiologic considerations. Ophthalmology 91:315 – 20

6.Browning DJ (1991) Risk of missing angle neovascularisation by omitting screening gonioscopy in patients with diabetes mellitus. Am J Ophthalmol 112:212

7.Browning DJ, Scott AQ, Peterson CB, Warnock J, Zhang Z (1998) The risk of missing angle neovascularisation by omitting screening gonioscopy in acute retinal vein occlusion. Ophthalmology 105:776 – 84

8.Chalam KV, Gandham S, Gupta S, Tripathi BJ, Tripathi RC (2002) Pars plana modified Baerveldt implant versus neodymium:YAG cyclophotocoagulation in the management of neovascular glaucoma. Ophthalmic Surg Lasers 33:383 – 393

9.Chen TC, Ahn Yuen SJ, Sangalang MA, Fernando RE, Leuenberger EU (2002) Retrobulbar chlorpromazine injections for the management of blind and seeing painful eyes. J Glaucoma 11:209 – 13

10.Custer PL, Reistad CE (2000) Enucleation of blind, painful eyes. Ophthalmic Plast Reconstr Surg 16:326 – 9

11.D’Amico DJ, Goldberg MF, Hudson H, Jerdan JA, Krueger DS, Luna SP, Robertson SM, Russel S, Singerman L, Slakter JS, Yannuzzi L, Zilliox P, Anecortave Acetate Clinical Study Group (2003) Anecortave acetate as monotherapy for treatment of subfoveal neovascularisation in age-related macular degeneration: twelve-month clinical outcomes. Ophthalmology 110:2372 – 83

12.De Gottrau P, Holbach LM, Naumann GOH (1994) clinicopathological review of 1146 enucleations (1980 – 1990). Br J Ophthalmol 78:260 – 5

13.Eid TE, Katz LJ, Spaeth GL, Augsburger JJ (1997) Tubeshunt surgery versus neodymium:YAG cyclophotocoagulation in the management of neovascular glaucoma. Ophthalmology 104:1692 – 700

14.Gasch AT, Foster CS, Grosskreutz CL, Paquale LR (2000) Postoperative sympathetic ophthalmia. Int Ophthalmol Clin 40:69 – 84

15.Genaidy M, Kazi AA, Peyman GA, Paissos-Machado E, Farahat HG, Williams JI, Holroyd KJ, Blake DA (2002) Effect of squalamine on iris neovascularisation in monkeys. Retina 22:772 – 8

16.Gragoudas ES, Adamis AP, Cunningham ET Jr, Feinsod M, Guyer DR, VEGF Inhibition Study in Ocular Neovascularisation Clinical Trial Group (2004) Pegaptanib for neovascu-

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II 18

18.1 Introduction

Intravitreal injection was reported by Ohm in 1911 as a technique to introduce air for retinal tamponade and repair of retinal detachment [28]. Intravitreal administration of pharmacotherapies dates to the mid-1940s with the use of penicillin to treat endophthalmitis [34, 35]. Since that time, use of the intravitreal injection technique has steadily increased, with its usage being focused primarily on the treatment of retinal detachment [7, 32], endophthalmitis [8, 31], and cytomegalovirus (CMV) retinitis [13, 43]. The increasing confidence in the efficacy and safety of intravitreal injections, in conjunction with the development of additional pharmacotherapies, has led to a recent rapid increase in the use of this technique for the administration of various pharmacotherapies (e.g., ranibizumab [6], pegaptanib sodium [9, 41, 42]) for age-related macular degeneration (AMD) and intravitreal triamcinolone for macular edema associated with a variety of etiologies, such as diabetic retinopathy [21], central retinal vein occlusion [10, 36], branch retinal vein occlusion [5, 17, 30, 37], uveitis [2, 44], and birdshot retinochoroidopathy [22].

18.2Risk of Endophthalmitis Associated with the Intravitreal Injection Procedure

With the recent widespread use of the intravitreal injection technique, there has been increased concern regarding the risk of endophthalmitis following intravitreal injection. The risk of endophthalmitis in eyes with CMV retinitis treated with intravitreal injection has been estimated to be 1.3 % per eye and 0.1 % per injection [16]. The risk of endophthalmitis following intravitreal triamcinolone acetonide injection has been estimated to be approximately 0.8 % for non-infectious endophthalmitis [16, 24, 25] and 0.6 – 0.16 % for infectious endophthalmitis [16, 26]. In general, endophthalmitis has been reported very rarely after intravitreal injection of gas or agents other than antiviral agents and triamcinolone acetonide, with a combined prevalence of approximately 0.1 % for all other compounds [16]. Combined analysis of two concurrent prospective, randomized, dou- ble-masked, multicenter, controlled clinical trials of intravitreal pegaptanib therapy for subfoveal choroidal neovascularization secondary to age-related macular degeneration demonstrated that the rate of endophthalmitis was 12/890 (1.3 %) patients over a

54-week period (the protocol included an intravitreal injection of pegaptanib into one eye of each patient every 6 weeks for 48 weeks) [9]. Eight of the 12 cases of endophthalmitis occurred during the first year of

18 II the study; after protocol changes were made relating to the injection procedure (e.g., use of a sterile eyelid speculum, a sterile drape, and gloves), no further cases of endophthalmitis occurred. This suggests that the injection technique is important in reducing the risk of endophthalmitis following intravitreal injection. Strategies that may be important in reducing the risk of endophthalmitis include attention to issues before, during, and after the injection. Guidelines developed as a result of round-table deliberations conducted after a review of published and unpublished studies and case series are summarized in Tables 18.1 and 18.2 [1].

Table 18.1. Guideline areas with strong agreement

Povidone-iodine for ocular surface, eyelids, and eyelashes

Use speculum and avoid contamination of the needle with eyelashes or eyelid margin

Avoid extensive massage of eyelids either preor postinjection (to avoid expressing meibomian glands)

Avoid injecting patients who have active eyelid or ocular adnexal infection

Dilate pupil

Use adequate anesthetic for a given patient (topical drops and/or subconjunctival injection)

Avoid prophylactic or postinjection paracentesis

Table 18.2. Guideline areas with no clear consensus

Most did not want to use a povidone-iodine flush, and preferred drops; no benefits attributed to waiting for the povidone-iodine to dry

Most did not use a sterile drape

Most advocated use of gloves

Use of preor postinjection topical antibiotics – little published scientific data to support reduction in endophthalmitis

Intraocular pressure (IOP) may be checked following injection – no agreement on IOP level at which physicians are comfortable to discharge patient

Dilated funduscopic examination can be performed following injection to confirm central retinal artery perfusion and intraocular location of drug.

No consensus on whether patients are competent to selfreport signs and symptoms of endophthalmitis or other adverse events; no consensus regarding the need for clinical follow-up examination versus telephone interchange with physician or nurse

18.3Injection Procedure Guidelines (Figs. 18.1 – 18.9)

reported risk factors for endophthalmitis and should be considered. Ocular surface bacteria may be the most common sources of bacteria causing postoperative endophthalmitis [3, 12, 20, 20, 38]. Thus, one strategy to reduce the risk of endophthalmitis is to reduce or eliminate the bacteria on the patient’s ocular surface and eyelids. While this may be achieved in various ways (povidone-iodine, topical antibiotics, eyelid hygiene and sterile isolation of the surgical site), povidone-iodine is the only agent that has been demonstrated to reduce the risk of postoperative endophthalmitis in a prospective study of cataract surgery [37]. It is unknown whether the application of povidone-iodine in the form of drops versus a flush impacts on the ability of this agent to prevent endophthalmitis. Lid scrubs have been reported to be associated with a significant increase in bacterial flora [4]; thus, excessive eyelid manipulation should be avoided (although the efficacy of lid scrubs in

Fig. 18.1. Dilated and telangiectatic vessels along lower eyelid margin consistent with significant meibomian gland disease. This patient’s eyelid disease was treated prior to administering an intravitreal injection of medication

Active external infection, including significant blepharitis, should be treated prior to injection. In addition, eyelid abnormalities such as ectropion are

Fig. 18.2. Topical anesthetic eyedrops are instilled into the eye before the povidone-iodine eyelid scrubs are performed since povidone-iodine can cause ocular discomfort

combination with povidone-iodine has not been reported). Since true contact allergy to povidoneiodine is rare, a reported history of such an allergy should be verified with a skin patch test.

Topical antibiotics have been demonstrated to reduce ocular surface bacteria significantly, but have not been proven to have a significant impact on reducing the risk of endophthalmitis [11, 15, 29, 40]. In a study of 35 patients who underwent intraocular surgery [15], a combination of antibiotics and povi- done-iodine resulted in 83 % of eyes having sterile cultures, compared to 40 % of eyes treated with povi- done-iodine alone and 31 % of eyes treated with antibiotic alone (a solution consisting of polymyxin B sulfate, neomycin sulfate, and gramicidin); these results provide evidence of a synergistic effect between antibiotics and povidone-iodine.

Fig. 18.6. A cotton-tipped swab soaked in sterile xylocaine 2 % is held against the injection site to achieve local anesthesia

During the injection procedure, the use of a sterile lid speculum is recommended in order to avoid needle contact with lids and lashes. The use of a sterile drape is optional but gloves, part of universal precautions, are appropriate. Sterile topical anesthetic is administered as the first step in the procedure. Ophthalmologists may consider subconjunctival anesthesia, but this requires additional instrumentation and manipulation which may be associated with increased surface flora. If subconjunctival anesthesia is used, keep in mind that the needle used for intravitreal injection passes through the subconjunctival space filled with anesthetic and that surface bacteria may have been introduced beneath the conjunctiva.

Fig. 18.7. Sterile calipers are used to measure and mark the desired distance posterior to the limbus

Fig. 18.9. We generally measure the intraocular pressure following intravitreal injection although this is not mandatory; it is important to perform a dilated funduscopic examination following the injection procedure to confirm central retinal artery perfusion and intraocular location of drug (when possible), as well as to investigate for such injection-related complications as retinal tear, retinal detachment, or vitreous hemorrhage

Fig. 18.8. The eye is stabilized with a cotton-tipped swab during the injection procedure. The cotton-tipped swab can then be rolled over the injection site following the injection to minimize reflux of drug and/or liquid vitreous

Although lidocaine gel has been used with increased frequency for anterior segment surgery cases in recent years, and has been reported as providing satisfactory patient comfort during intravitreal injection procedures while causing less chemosis and hemorrhage than subconjunctival anesthesia [19], another study identified lidocaine gel as a potential risk factor for endophthalmitis following cataract surgery [23]. Lidocaine gel may serve as a barrier, reducing the ability of povidone-iodine to contact the ocular surface and reduce the risk of endophthalmitis. Even if povidone-iodine is administered prior to lidocaine gel (in an attempt to bypass the potential

barrier effect), it should be recognized that the commercially available lidocaine gel is not prepared as a sterile formulation and, therefore, the injection needle may become contaminated as it passes through the lidocaine gel and before it enters the intravitreal cavity. Care should be taken to avoid pressure to the eyelids, eyelid margins, and the adnexa due to the potential for release of resident bacteria. According to one study [14], 13 % of the ophthalmic drugs obtained from multiple-use medication bottles tested positive for bacteria and 21 % of the bottle tips were culture-positive. Single-use medication bottles should be considered for pupil dilation and anesthesia, although this is not critical if povidone-iodine is applied after the instillation of anesthetic and dilating agents.

After the injection procedure, topical antibiotics have been shown to lower the number of bacteria on the ocular surface and may enter the anterior chamber; however, their efficacy in reducing the risk of endophthalmitis has not been proven. Prophylactic antibiotics, if administered, should provide appropriate coverage for likely pathogens and be relatively low cost.

18.4 Guidelines for Follow-up

Because of the relatively low risk of endophthalmitis associated with intravitreal injection, no study has compared different strategies for follow-up. As clinicians’ comfort level with this procedure has increased,

most clinicians no longer evaluate patients one day following intravitreal injection. However, patients should be instructed to contact the ophthalmologist immediately with signs and symptoms of complications (e.g., increased ocular redness or discomfort compared to right after the injection, decreased vision) and it is prudent to contact the patient within 1 week of the procedure to inquire about such symptoms.

18.5Non-infectious Endophthalmitis (Figs. 18.10, 18.11)

Both infectious and non-infectious endophthalmitis have been reported following intravitreal injections. Non-infectious endophthalmitis may represent dispersion of drug crystals (such as has been reported in association with triamcinolone acetonide) [24] in the anterior chamber and vitreous cavity or an acute inflammatory reaction to a component in the drug formulation. The incidence of non-infectious endophthalmitis following intravitreal triamcinolone acetonide injection has been reported to range from 0.2 % to 1.6 % [18, 27, 33, 39]. Typical clinical features

of non-infectious endophthalmitis include absence of pain and eyelid edema and no increased conjunctival injection compared with that present immediately after injection. Such patients should be moni-

tored carefully to rule out progressive inflammation II 18 due to early endophthalmitis. In addition, patients

should be instructed to contact the ophthalmologist immediately if they note any change in their ocular symptoms, such as pain, decreased vision, or increased ocular redness compared to that present right after the injection procedure.

18.6 Summary

Intravitreal injection is becoming an increasingly widespread technique in the management of a variety of posterior segment diseases and is an important part of the retina specialist’s armamentarium. In order to optimize the outcomes associated with intravitreal injection, careful attention should be paid to reducing the risk of postinjection endophthalmitis. Ultimately, the outcomes of treatment depend not only on the safety and efficacy of the pharmacotherapy being delivered, but also on the safety and potential adverse events associated with the procedure itself.

Fig. 18.10. Pseudohypopyon in a patient following intravitreal triamcinolone acetonide injection

Fig. 18.11. Same eye as in Fig. 18.10 following spontaneous improvement of the pseudohypopyon (no treatment was administered)

References

1.Aiello LP, Brucker AJ, Chang S, et al. (2004) Evolving guidelines for intravitreous injections. Retina 24:S3–S19

2.Antcliff RJ, Spalton DJ, Stanford MR, et al. (2001) Intravitreal triamcinolone for uveitic cystoid macular edema: an optical coherence tomography study. Ophthalmology 108: 765 – 772

3.Bannerman TL, Rhoden DL, McAllister SK, et al. (1997) The source of coagulase-negative staphylococci in the Endophthalmitis Vitrectomy Study. A comparison of eyelid and intraocular isolates using pulsed-field gel electrophoresis. Arch Ophthalmol 115:357 – 361

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intravitreal triamcinolone acetonide injection. Retina 23: 686 – 691

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31.Peyman GA, Vastine DW, Raichand M (1978) Experimental aspects and their clinical application. Ophthalmology 85:374 – 385

32.Rosengren B (1952) 300 cases operated upon for retinal detachment; method and results. Acta Ophthalmol (Copenh) 30:117 – 122

33.Roth DB, Chieh J, Spirn MJ, et al. (2003) Non-infectious endophthalmitis associated with intravitreal triamcinolone injection. Arch Ophthalmol 121:1279 – 1282

34.Rycroft B (1945) Penicillin and the control of deep intraocular infection. Br J Ophthalmol 29:57 – 87

35.Schneider J, Frankel SS (1947) Treatment of late postoperative intraocular infections with intraocular injection of penicillin. Arch Ophthalmol 37:304 – 307

36.Scott IU, Ip MS (2005) It’s time for a clinical trial to investigate intravitreal triamcinolone for macular edema associated with retinal vein occlusion: the SCORE study. Arch Ophthalmol 123:581 – 582

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38.Speaker MG, Milch FA, Shah MK, et al. (1991) Role of external bacterial flora in the pathogenesis of acute postoperative endophthalmitis. Ophthalmology 98:639 – 649; discussion 650

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40.Ta CN, Egbert PR, Singh K, et al. (2002) Prospective randomized comparison of 3-day versus 1-hour preoperative ofloxacin prophylaxis for cataract surgery. Ophthalmology 109:2036 – 2041

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Core Messages

The purposes of clinical retinopathy grading are:

–Identification of eyes that have reached a threshold for treatment of retinopathy

–Definition of an appropriate follow-up interval, to minimize the risk of progression to levels of retinopathy above a treatment threshold before follow-up, estimated on the basis of the current level of retinopathy and its likely rate of progression

–Staging of microvascular complications for use in the management of systemic conditions

The purposes of research retinopathy grading are:

–To assess retinopathy levels and retinopathy progression with high sensitivity and reproducibility using a grading scale with a documented relation to long term visual outcome

The grading of diabetic retinopathy is based on the concept that a hierarchy of stages can be defined, where the higher the grade, the higher the risk of suffering visual loss. The grading scale reflects the natural course of the disease in its unrelenting and most devastating form. In reality, diabetic retinopathy can regress both spontaneously and after therapeutic intervention. To construct or validate a grading scale, rates of progression to visual loss or another endpoint that is meaningful to the patient must be measured. Grading scales constructed for scientific and regulatory purposes, such as the study of new interventions, are made with the purpose of achieving maximum sensitivity for change in retinopathy. Interventional trials may then result in selected grades being validated and found useful for guiding interventions such as photocoagulation for proliferative diabetic retinopathy or diabetic macular edema. The timely identification of patients who reach interventional thresholds is the purpose subserved by simpler grading scales used in clinical screening practice.

In the scientific and regulatory environment, diabetic retinopathy grading is an accepted surrogate measure of outcome, but only because it has a documented relation to visual outcome. Interventions that are potent enough to improve visual outcome can obviously be assessed on a functional measure rather than a surrogate morphological endpoint.

In the clinical management of diabetic retinopathy, intervention should be made or at least consid-

ered before visual loss has occurred. Thus, in principle, measures of visual function are not sensitive enough to detect a need for treatment, unless the retinopathy has progressed beyond threshold. Clinical retinopathy assessment is also used to estimate the safe follow-up interval (time to next screening visit) and to decide when to stop treatment.

Retinopathy grading for scientific purposes is done based on fundus photography because of the need for lasting documentation. Stereoscopic fundus photography is the reference standard. In clinical practice, stereoscopic slit-lamp biomicroscopy using a corneal contact lens is the best standard of care. Direct ophthalmoscopy is of little use other than determining the absence of retinopathy because the field of view is restricted and because the lack of stereoscopic viewing makes the direct observation of preretinal proliferations and macular edema difficult or impossible.

Systematic evaluation of the diabetic fundus begins with the identification of the number and location of fundus lesions by class (hemorrhage, hard exudate, cotton wool spot, intraretinal microvascular abnormality, neovascular proliferation, fibrosis, edema, other lesions). This information is then used to determine the severity of retinopathy, which summarizes the information about individual lesion types in a given eye (per-eye grading) or in a given patient (per-patient grading) where usually the severity score for the most severely affected eye is used to represent that patient’s severity score. Severi-